EPILEPTIC ENCEPHALOPATHY - INFANT, CHILDREN AND ADULT

Infant, childhood and Adult epileptic encephalopathies

1. EPILEPTIC ENCEPHALOPATHY ‹#›

2. INTRODUCTION A group of heterogeneous brain disorders occurring at a critical period of brain development, where frequent abnormal ictal and/or interictal EEG epileptiform activity. These are characterized by epileptiform activity with developmental slowing and regression . ‹#›

3. PATHOPHYSIOLOGY COMMON FEATURES : Starts at an early age Intractable seizure usually Cognitive, behavioral and neurological deficits Sometimes early death EEG CHANGES Burst suppression - Neonates Hypsarrhythmia - Infants Slow generalised spike and wave (GSWD) - child ‹#›

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5. DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES SYNDROME BY AGE ONSET NEONATE Early-infantile developmental and epileptic encephalopathy (EIDEE) Early myoclonic encephalopathy infant Epilepsy of infancy with migrating focal seizures (EIMFS) Infantile epileptic spasms syndrome ( WEST SYNDROME ) Dravet syndrome ‹#›

6. Early-infantile developmental and epileptic encephalopathy (EIDEE) aka OHTAHARA syndrome Within the first three months of life. Frequent, often drug-resistant seizures. Abnormal neurological examination findings, including issues with posture, tone, or movement. Moderate to profound developmental impairments that become apparent over time. ‹#›

7. Diagnosis of EIDEE requires one or more of the following seizure types: 1. Tonic seizures. 2. Myoclonic seizures. 3. Epileptic spasms. 4. Sequential seizures, may include tonic, clonic, and/or autonomic components, as well as automatisms without a single predominant seizure type. Varied underlying etiologies including genetic, metabolic, and structural ‹#›

8. EEG: Interictal-Either burst suppression or multifocal discharges, Diffuse slowing The burst-suppression pattern may disappear with age, but the EEG will remain abnormal. Ictal: The pattern depends on seizure type. In the neonatal period, ictal patterns are focal or asymmetric. With tonic seizures the burst-suppression pattern attenuates with the emergence of low-voltage, high-frequency fast activity ‹#›

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10. Structural brain abnormalities are an important and frequent cause of EIDEE and should be sought in all children. Causative pathogenic gene variants can be identified in more than half of patients with EIDEE. KCNQ2- sequential seizures SCN2A-DEE - sequential seizures with predominantly tonic and autonomic features. STXBP1-DEE asymmetric tonic or sequential seizures ‹#›

11. Half of children die in infancy or childhood. No effective treatment Vigabatrin and zonisamide showed some benefit Invasive surgery, such as partial resection or complete hemispherectomy. ‹#›

12. EARLY MYOCLONIC ENCEPHALOPATHY Onet < 3 months Male = Female Etiology - inborn errors of metabolism. mc - nonketotic hyperglycinemia, methylmalonic acidemia. ‹#›

13. Seizures - Erratic myoclonus f/b simple focal seizures f/b tonic seizures Erratic myoclonus - shift typically from one part of body to another in a random asynchronous fashion. CT and MR - related to etiology, grossly normal or have enlargement of one hemisphere. ‹#›

14. Interictal EEG - suppression - burst activity, evolve into hypsarrhythmia after 3 - 5 months of life. ‹#›

15. Prognosis is poor > 50% die within weeks or months No effective therapy ‹#›

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17. EPILEPTIC ENCEPHALOPATHY SYNDROMES IN INFANCY ‹#›

18. Epilepsy of infancy with migrating focal seizures (EIMFS) Frequent partial seizures of multifocal onset with autonomic or motor involvement. Seizures can originate in either hemisphere and may migrate between cortical regions during an episode. ‹#›

19. P rimarily genetic, prominently involving the KCNT1106 gene, along with over 25 other associated genes. The prognosis - poor, characterized by neurological disabilities & reduced life expectancy. Occurs within the first six months of life ‹#›

20. Both males and females are equally affected by this condition. Most patients develop microcephaly by 1 year of age Development may be normal at onset. ‹#›

21. P rognosis - drug-resistant seizures & severe neurological impairments - poor. With significant developmental and motor disabilities, and reduced life expectancy.  Focal motor clonic or tonic seizures are mandatory for diagnosis. ‹#›

22. Focal seizures show a migration pattern on EEG, which might be missed if a prolonged video-EEG is not performed. Status epilepticus is common. ‹#›

23. Ictal recording shows a migrating pattern (this might be missed if a prolonged video EEG is not performed) Interictal: Multifocal discharges. ‹#›

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25. Familial inheritance is rare De novo  gene abnormalities are most commonly implicated. KCNT1 is the major gene and reported in half of cases. Other genes associated with this syndrome include mainly SCN1A, SCN2A, SLC12A5, BRAT1, and TBC1D24 ‹#›

26. Infantile epileptic spasms syndrome (IESS) IESS also known as West syndrome - infants presenting with epileptic spasms who do not fulfil all the criteria for West syndrome ‹#› E pileptic spasms H ypsarrhythmia D evelopmental stagnation or regression

27. O nset of epileptic spasms between 3 to 12 months of age, Both sexes are affected, with a higher incidence in males The estimated incidence of IESS is 30/100 000 liveborn infant etiology - cerebral malformation,infection, hemorrhage, hypoxic ischemic injury. ‹#›

28. Epileptic spasms are mandatory for the diagnosis of IESS, and consist of brief tonic contractions of axial muscles, each typically lasting <3 s, which may be flexor, extensor, or mixed. occurs in cluster 1-30/day ‹#›

29. EEG - Interictal , hypsarrhythmia (chaotic, high amplitude, excessive slowing, multifocal epileptiform discharges) is often seen and the yield of detection is greatest if nonREM (rapid eye movement) sleep is recorded. A consistent focal epileptiform discharge or focal fast activity should suggest an underlying structural abnormality ‹#›

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31. TREATMENT First line Vigabatrin Valproate, levetiracetam , topiramate, zonisamide, lamotrigine and benzodiazepines Ketogenic diet is helpful Hemispherectomy - medically intractable. No specific AED showed long term developmental outcome. ‹#›

32. Dravet syndrome (DS) DS (previously known as Severe Myoclonic Epilepsy of Infancy), presents in the first year of life in a normal child. Male : Female - 2:1 SCN1A (found in over 80% of cases) - sporadic ‹#›

33. Tetrad of seizures : E arly onset infantile febrile clonic convulsions Myoclonic jerks A typical absence Complex focal seizures ‹#›

34. Precipitating factors : Febrile illness, warm environment, photic stimulation. Inter-ictal EEG. Abnormal slow background with frequent asymetrical paroxyms of polyspikes. ‹#›

35. Treatment : Intial - Phenobarbital, sodium valproate others - topiramate, clonazepam, clobazam Short course of streroid and keotgenic diet might be helpful. ‹#›

36. EPILEPTIC ENCEPHALOPATHY SYNDROMES IN CHILDHOOD ‹#›

37. Epilepsy with myoclonic atonic seizures(EMAtS) EMAtS, previously identified as Doose syndrome Manifests in early childhood During the active seizure phase, children often experience developmental stagnation or regression, which improves with effective seizure management. ‹#›

38. children between the ages of 2 and 6 yrs Boys are more affected. One quarter of children have a history of a febrile seizure` Onset is often abrupt. Generalized tonic-clonic and Myoclonic are the most often types of seizures occurred . ‹#›

39. S eizures often are drug resistant` Majority of children with initially drug-resistant seizures can achieve remission within three years and can discontinue anti seizure medication. ‹#›

40. Myoclonic - atonic seizures are mandatory to diagnose . Tonic seizures appears in some patients later in course and is associated with very poor outcome. NCSE is also common - manifests as impaired awareness (hours to days ) with atypical absence, myoclonic and atonic features, assoc with somnolence, unsteadiness, drooling, speech disorders. ‹#›

41. The EEG analysis reveals Interictal abnormalities comprised of generalized 2– 6-Hz spike-and-wave or polyspike-and-wave complexes often occurring in bursts lasting 2–6 s are seen. ‹#›

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43. During non convulsive status epilepticus, the EEG shows long runs of high-amplitude, 2–3-Hz irregular, generalized spike-and-wave activity, with background slowing. ‹#›

44. Lennox–Gastaut syndrome(LGS) S evere form of epilepsy that arises from various etiologies. It manifests during a critical developmental period in childhood, characterized by high-frequency, synchronized brain activity across bilateral networks . ‹#›

45. D efined by the occurrence of multiple types of drug-resistant seizures, with at least one seizure type being tonic, atonic, atypical absence and myoclonic jerks Cognitive and behavioural abnormalities. diffuse slow spike-and-wave and generalized paroxysmal fast activity on EEG. ‹#›

46. onset 1-7 years, peak 3-5 years. Often exhibit pre-existing developmental impairments prior to the onset of seizures, but developmental stagnation or decline can occur with onset of frequent seizures. ‹#›

47. It continues into adulthood with seizures resistant to medication` Developmental slowing, plateauing, or regression, culminating in moderate to severe intellectual disability in >90% of patients` ‹#›

48. Tonic seizures, consisting of axial and limb muscle contraction lasting from 3s to 2 mins are mandatory for diagnosis and more prominent in sleep. In addition to tonic seizures, a second seizure type is mandatory for diagnosis of LGS many include the following : SEIZURES ‹#›

49. Atypical absence seizure Atonic seizures Myoclonic seizures Focal impaired awareness seizures GTCS NCSE Epileptic spasms ‹#›

50. The EEG - abnormal, with diffuse theta – delta slowing. Two interictal patterns are mandatory for the diagnosis of LGS: (a) Generalized slow spike-and-wave characterized by spikes (<70ms)or sharp waves (70-200ms), followed by negative high-voltage slow waves, at a frequency of ≤2.5 Hz. After the age of 16  years, the majority of patients no longer exhibit the typical slow spike and-wave pattern ‹#›

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52. (b) Generalized paroxysmal fast activity Pattern consists of bursts of diffuse or bilateral fast (10 Hz or more) activity often seen during sleep. These typically are brief, lasting a few seconds or less ‹#›

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54. Structural causes are the commonest etiology, MRI at onset is strongly recommended, as it impacts on treatment decision making. Focal or cortical malformations, tuberous sclerosis complex, tumours, acquired such as Hypoxic ischemic encephalopathy. ‹#›

55. GENETICS Genetic testing should also be considered for patients with structural brain disorders suggestive of an underlying genetic cause. If no etiology is found after clinical examination and MRI, whole genome sequencing or epilepsy gene panel is advised. ‹#›

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57. DEE-SWAS and EE-SWAS DEE-SWAS and EE-SWAS are conditions marked by cognitive, language, behavioral, and motor regression linked to spike-and-wave activity during sleep. Sleep EEG must be performed to confirm the diagnosis. There is no mandatory seizure type. Seizure type is dependent on the underlying etiology. ‹#›

58. DEE-SWAS is a condition observed in individuals with pre-existing neurodevelopmental disorders. It is characterized by a documented deterioration in cognitive, language, behavioral, and motor functions, accompanied by notable spike-and-wave complex activity during sleep. EE-SWAS is identified in patients with previously normal development, characterized by the activation of slow (1.5–2 Hz) spike-and-wave complexes during non-rapid eye movement (N-REM) sleep. ‹#›

59. DEE-SWAS and EE-SWAS are rare, accounting for 0.5%– 0.6% of all epilepsy presentations seen at pediatric tertiary epilepsy centers . Typically manifest seizures between the ages of 2 and 12, peaking at 4 to 5 years. EEG changes show spike-and-wave patterns during sleep within 1 to 2 years Both conditions affect males and females equally. Structural brain lesions are a risk factor for DEE-SWAS and EE-SWAS therefore, neuroimaging, particularly MRI, is recommended whenever possible. ‹#›

60. EEG pattern: Focal or diffuse slowing and contains focal or multifocal abnormalities, but it may be normal. ‹#›

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62. In drowsiness and sleep, with slow (1.5–2 Hz) spike-and-wave abnormalities in N-REM sleep. Typically sleep in Stage II of sleep. An overnight sleep EEG may be required, as slow wave sleep may not be achieved on an outpatient sleep EEG. ‹#›

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64. Neuroimaging may be normal or demonstrate underlying structural brain abnormalities. Some cases have a genetic basis. ‹#›

65. Febrile infection-related epilepsy syndrome(FIRES) FIRES (formerly known as acute encephalitis with refractory, repetitive partial seizures or devastating epileptic encephalopathy in school-aged children), is a significant cause of new onset refractory status epilepticus, primarily affecting children and adolescents. ‹#›

66. A prior febrile infection can precede the sudden onset of super refractory status epilepticus by 24 hours to 2 weeks. The initial phase, characterized by a high seizure burden, may last from 1 to 12 weeks and is associated with considerable mortality and morbidity. Survivors are left with drug resistant epilepsy with intellectual and learning disabilities. ‹#›

67. This is a rare syndrome, which is likely underrecognized, with an estimated incidence of 1 per million FIRES predominantly affects school-aged children, typically around 8 years old, with a range from 2 to 17 years. Both sexes are affected, with a slight male predominance. All children have a history of a prior febrile infection, most commonly upper respiratory or gastrointestinal, between 24 h and 2 weeks before onset of refractory status epilepticus. ‹#›

68. Approximately one third of survivors have normal or borderline cognition (often learning disorders), one third have mild to moderate intellectual disability, and one third have severe to profound disability or are vegetative In the chronic phase, many patients will have evidence of motor dysfunction. Focal or multifocal seizures are mandatory for diagnosis and may evolve to bilateral tonic–clonic seizures ‹#›

69. The EEG : Slowing of the background activity with multifocal epileptiform abnormalities and frequent, focal electrographic and electroclinical seizures The EEG background activity is typically abnormal, with slowing and multifocal abnormalities. Recurrent extreme delta brush, consisting of a paroxysmal beta– delta complex of 15–18-Hz beta superimposed on 1–3- Hz delta in the frontal and central head regions, is often seen ‹#›

70. ‹#› A typical seizure pattern, consisting of focal activity of >10 Hz of low to moderate amplitude, evolving to well-formed, rhythmic spikes and spike-and-wave complexes, is seen. This disorder is not suspected to be genetic, and no causal genes have been identified. Examination of cerebrospinal fluid (CSF) is required to exclude infection. The CSF is typically normal but may show a mild pleocytosis.

71. Hemiconvulsion - hemiplegia- epilepsy syndrome HHE is a rare consequence of focal motor status epilepticus in infancy and early childhood., occurring in context of febrile illness in children <4 years of age. Neuroradiological study at time of status epilepticus shows unilateral edematous swelling of the affected hemisphere, followed by atrophy. ‹#›

72. Associated with focal seizures , drug resistant epilepsy. Majority have a permanent motor deficit, Underlying mechanism or etiology are not understood. HHE is rare syndrome and its incidence has declined over past 14 years. ‹#›

73. Age onset is < 4 years and there is no sexual predilection. Children present with prolonged focal status epilepticus and develop immediate hemiparesis. Diagnosis is considered when persistent hemiplegia observed after febrile status epilepticus in a child younger than 4 years. ‹#›

74. First seizure - focal clonic febrile status epilepticus. EEG - during acute focal status epilepticus, ictal discharge characterized by rhythmic (2-3 Hz) slow waves Background activity may be normal at onset, in chronic phase there is excess slowing and epileptiform abnormalities. ‹#›

75. MRI s/o hemispheric signal abnormalities with T2 hyperintensity and restricted diffusion, pred. subcortical white matter. ‹#›

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77. CONCLUSION ‹#›